Glaucoma is a slowly progressive blinding disease usually associated with chronic elevation of intraocular pressure (IOP). Sufficiently high and persistent intraocular pressure is believed to result in damage to the optic disc at the juncture of the optic nerve and retina, resulting in degeneration of retinal ganglion cells and blindness characteristic of glaucoma. However, the mechanism whereby IOP elevation (also known as ocular hypertension) leads to glaucoma is not well understood. Additionally, a fraction of patients with typical visual field loss associated with glaucoma do not show abnormal elevated IOP levels (known as low-tension or normal-tension glaucoma).
Glaucoma is primarily classified as open-angle, closed-angle, or congenital, and further classified as primary and secondary. Glaucoma is treated with a variety of pharmacological and surgical approaches. In cases where glaucoma is associated with ocular hypertension, pharmacological treatment comprises adrenergic agonists (epinephrine, dipevefrin, apraclonidine), cholinergic agonists (pilocarpine), beta blockers (betaxolol, levobunolol, timolol), carbonic anhydrase inhibitors (acetazolamide) or more recently, prostaglandin analogues (latanoprost, Lumigan™) and alpha adrenergic agonists (brimonidine). These pharmacological approaches help restore the IOP to a normotensive state either by inhibiting the production of aqueous humor by the ciliary body, or facilitating aqueous humor outflow across the trabecular meshwork. The congenital form of glaucoma rarely responds to therapy and is more commonly treated with surgery. In narrow angle glaucoma, the aqueous outflow is enhanced by freeing of the entrance to the trabecular space at the canal of Schlemm from blockade by the iris, as a result of the drug-induced contraction of the sphincter muscle of the iris (Taylor, pp. 123-125, in The Pharmacological Basis of Therapeutics, 7th Ed, Eds., A. G. Gilman, L. S. Goodman, T. W. Rall, and F. Murad, MacMillan Publishing Company, New York, (1985)).
In wide-angle, or chronic simple, glaucoma, the entry to the trabeculae is not physically obstructed; the trabeculae, a meshwork of pores of small diameter, lose their patency. Contraction of the sphincter muscle of the iris and the ciliary muscle enhances tone and alignment of the trabecular network to improve resorption and outflow of aqueous humor through the network to the canal of Schlemm (Watson, Br. J. Opthalmol. 56: 145-318 (1972); Schwartz, N. Engl. J Med., 290: 182-186 (1978); Kaufman, et al., Handbook of Experimental Pharmacology 69: 149-192 (1984)).
Acute congestive (narrow angle) glaucoma is nearly always a medical emergency in which the drugs are essential in controlling the acute attacks, but long-range management is usually based predominantly on surgery (peripheral or complete iridectomy). By contrast, chronic simple (wide-angle) glaucoma has a gradual, insidious onset and is not generally amenable to surgical improvement; and control of intraocular pressure depends upon permanent therapy.
Acute congestive glaucoma may be precipitated by the injudicious use of a mydriatic agent in patients over 40 years, or by a variety of factors that can cause pupillary dilatation or engorgement of intraocular vessels. Signs and symptoms include marked ocular inflammation, a semidilated pupil, severe pain, and nausea. The therapeutic objective is to reduce the intraocular pressure to the normal level for the duration of the attack. An anticholinesterase agent is instilled into the conjunctival sac with a parasympathomimetic agent for greatest effectiveness. A commonly used combination consists of a solution of physostigmine and salicylate, 0.5%, plus pilocarpine nitrate, 4%. Adjunctive therapy includes the intravenous administration of a carbonic anhydrase inhibitor such as acetozolamide to reduce the secretion of aqueous humor, or of an osmotic agent such as mannitol or glycerin to induce intraocular dehydration.
Therapy of chronic simple glaucoma and secondary glaucoma includes: (1) prostaglandin analogs (e.g. Xalatan®, Lumigan); (2) beta-adrenergic antagonists such as timolol maleate; (3) sympathomimetic agents (e.g. epinephrine, brimonidine); (4) cholinergic agents (e.g. pilocarpine nitrate, echothiophate iodide; and (5) carbonic anhydrase inhibitors (e.g. Dorzolamide®) (Dain Rauscher Wessels, Glaucoma in the 21st Century: New Ideas, Novel Treatments (2001)).
Latanaprost (Xalatan®) is a prostanoid agonist that is believed to reduce IOP by increasing the uveoscleral outflow of aqueous humor. Latanoprost is an isopropyl ester prodrug, and is hydrolyzed by esterases in the cornea to the biologically active acid. Xalatan® (0.005%) is prescribed for once-daily dosing and is shown to be equivalently effective as twice-daily dosing of 0.5% timolol. However, Xalatan® may gradually change eye color by increasing the amount of brown pigment in the iris. The long-term effect on the iris is unknown,. Eyelid skin darkening has also been reported in associated with the use of Xalatan®. In addition, Xalatan® may gradually increase the length, thickness, pigmentation, and number of eyelashes. Macular edema, including cystoid macular edema, has been reported during treatment with Xalatan®. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema ((Ophthalmic PDR, 315-316 (2001)).
Beta-Adrenergic antagonists effectively lower IOP when administered twice daily as a topical solution. The mechanism of reduction is through inhibition of the production of aqueous humor formed by the ciliary body. Topical timolol causes fewer adverse effects than the anticholinesterase agents. However, it may induce hyperaemia of the conjunctiva, burning, stinging, and superficial punctate keratitis (Van Buskirk, Ophthalmology 87: 447-450 (1980)). It may also reduce tear flow, causing dry eye syndrome (Coakes, et. al., Br. J. Ophthalmol 65: 603-605 (1981)). A more serious side effect of beta-blockers is cardiac failure, thus this class of IOP-lowering agent is not indicated with cardiopulmonary disease.
Alpha-Adrenergic agonists, such as brimonidine and apraclonidine, control IOP by reducing the production of aqueous humor as well as enhancing uveoscleral outflow (Burke & Schwartz, Survey of Ophthalmology 41:S9-S18 (1996)). Topical ophthalmic solutions are absorbed systemically and can produce dry mouth, ocular hyperemia, headache, and foreign body sensation (Hoyng and van Beek, Drugs 59: 411-434 (2000)).
The use of long-acting anticholinesterase agents is associated with a greater risk of developing lenticular opacities and untoward autonomic effects. Treatment of glaucoma with potent, long-acting anticholinesterase agents (including demecarium, echothiophate, and isoflurophate) for 6 months or longer is associated with a high risk of developing cataracts (Axelsson, et al., Acta Opthalmol. (Kbh.) 44: 421-429 (1966); de Roetth, J.A.M.A. 195: 664-666 (1966); Shaffer, et al., Am. J. Opthalmol. 62: 613-618 (1966)). Although development of cataracts is common in untreated comparable age groups, the incidence of lenticular opacities under such circumstances can reach 50%, with the risk increasing in proportion to the strength of the solution, frequency of instillation, duration of therapy, and age of patient (Laties, Am. J. Opthalmol. 68: 848-857 (1969); Kaufman, et al., pp. 149-192, in Pharmacology of the Eye, Handbook of Experimental Pharmacology, Vol. 69, Ed. M. L. Sears, Springer-Verlag, Berlin, (1984)).
Miscellaneous ocular side effects that may occur following instillation of anticholinesterase agents are headache, brow pain, blurred vision, phacodinesis, pericorneal injection, congestive iritis, various allergic reactions and, rarely, retinal detachment. When anticholinesterase drugs are instilled intraconjunctivally at frequent intervals, sufficient absorption may occur to produce various systemic effects that result from inhibition of anticholinesterase and butyryl-cholinesterase. Hence, cholinergic autonomic function may be enhanced, the duration of action of local anesthetics with an ester linkage prolonged, and succinylcholine-induced neuromuscular blockade enhanced and prolonged. Individuals with vagotonia and allergies are at particular risk.
Because the cholinergic agonists and cholinesterase inhibitors block accommodation, they induce transient blurring of far vision, usually after administration of relatively high doses over shorter duration. With long-term administration of the cholinergic agonists and anticholinesterase agents, the response diminishes due to a diminished number of acetylcholine receptors.
Long-acting anticholinesterase agents are not recommended when prostaglandin analogs, beta-adrenergic antagonists, sympathomimetic agonists, or other agents can control glaucoma.
Carbonic anhydrase inhibitors control IOP by inhibiting the formation of aqueous humor. Oral carbonic anhydrase inhibitors exhibit pronounced systemic side effects, but newer topical solutions have a better side effect profile. Frequent side effects associated with topical Dorzolamide® include burning and stinging, bitter taste, superficial punctate keratitis, and allergic reaction (Hoyng and van Beek, Drugs 59: 411-434 (2000)).
Other new agents have been assessed for treatment of glaucoma, including an A3 subtype adenosine receptor antagonist, a calmodulin antagonist, and an antiestrogen (WO 00/03741); an oligonucleotide which may be substituted, or modified in its phosphate, sugar, or base so as to decrease intraocular pressure (U.S. Pat. No. 5,545,626); and a class of pyrazine, pyrimidine, and pyridazine derivatives, substituted by a non-aromatic azabicyclic ring system and optionally by up to two further substituents (U.S. Pat. No. 5,219,849).
Various studies have documented the presence of P2 purinergic receptors in the eye. Activation of P2Y2 receptors in rabbit and human conjunctival cells was associated with an increase in mucin secretion (Jumblatt and Jumblatt, Exp. Eye Res. 67(3):341-6 (1998)). P2Y2 receptor agonists, such as ATP, cause mucin secretion, and mechanical stimulus of the cornea triggers local ATP release (Jensen et al., poster presentation at American Academy of Optometry annual meeting, December, 1999, Seattle, Wash.). Studies of P2 purinergic receptors in ocular ciliary epithelial cells demonstrated a P2U purinergic receptor, that was preferentially coupled to UTP and associated with the stimulation of phosphoinositide hydrolysis in both bovine pigmented and human non-pigmented epithelial cells (Wax, et al., Exp. Eye Res. 57: 89-95 (1993)). ATP significantly increased formation of inositol phosphates in bovine corneal endothelial cells (Crawford, et al., Current Eye Res., 12(4): 303-311 (1993) and in human ocular ciliary epithelial cells (Wax and Coca-Prados, Investig. Opthalmol. Vis. Science, 30 (7): 1675-1679 (1989)). Diadenosine tetraphosphate has been shown to lower intraocular pressure in rabbits (Peral, et.al., Investig. Opthalmol. Vis. Science, 41: S255 (2000). Alpha, Beta-Methylene adenosine triphosphate and beta, gamma methylene adenosine triphosphate also were shown to reduce intraocular pressure in rabbits (Pintor, et.al., Investig. Opthalmol. Vis. Science, 41: S255 (2000). Stimulation of P2Y2 purinergic receptors in bovine ciliary epithelium was coupled to a pertussis toxin-sensitive G protein and associated with the activation of phospholipase C, leading to mobilization of calcium from intracellular stores (Shahidullah, et al., Curr. Eye Res., 16(10): 1006-1016 (1997)). ATP was shown to cause a dose-dependent increase in intracellular calcium in the ciliary epithelial cells of the eye (Lee, et al., Exp. Eye Res., 48: 733-743 (1989)). Mitchell, et al. (Proc. Natl. Acad. Sci. U.S.A., 95: 7174-7178 (1998)) showed that both the bovine pigmented and nonpigmented ciliary epithelial cells store and release ATP and other purines that may effect aqueous humor outflow by paracrine and/or autocrine mechanisms.
As described above, agents commonly used to treat glaucoma may cause adverse side effects, such as eye pain, eye color darkening, headache, blurred vision or the development of cataracts. There exists a need for agents that are both safe and effective in the treatment of glaucoma. This invention provides a novel approach to reduce intraocular pressure and thereby treat glaucoma.